Chronic Stress, Glucocorticoids, and Progesterone in Brain Aging

有证据表明，长期/重复的行为压力会促进大脑衰老。这被认为是由于， 至少部分地应激相关的糖皮质激素（GC）分泌，其又结合糖皮质激素受体， 发挥转录和其他作用。一个关键的下游介质在这一信号通路，血清和- 糖皮质激素激酶1（Sgk 1）加速，女性性类固醇孕酮（P4）减弱， GC。然而，尽管慢性应激暴露与衰老和/或衰老相关的负面临床后果， 对于女性受试者，很少有研究探讨衰老如何改变应激反应， 压力可能加速大脑老化，压力加速老化依赖于GC的程度， 由Sgk1驱动，或由P4抑制。我们的初步数据表明，海马Sgk1被上调， 衰老、应激和白色少突胶质细胞中的GC，以及雌性激素孕酮（P4） 减弱压力/GC的影响，并可能作为一种内源性保护剂，随着女性年龄的增长而消失。 为了解决这些知识差距，我们提出了3个调查目标： 男性和女性中的应激或慢性GC;是否Sgk1的病毒过表达加重，或系统性P4 给药改善，应激加速老化;以及海马神经元的药理学敏感性是否 随着年龄或慢性应激/GC，组织中的GC和P4发生变化。认知和焦虑相关行为，血液 激素测量，以及一组新的205个海马基因，这些基因随着年龄的增长而发生强烈变化， 多项研究将用于测试应力/GC加速老化和干预效应，下游也将如此 灰质和白色物质Sgk 1表达和小胶质细胞对微损伤的反应--这两个过程被证明是 糖皮质激素敏感，并且在白色与灰质的初步数据中被夸大。因此，拟议的 研究将基本上产生第一个全面的测试假设，慢性压力加速 转录脑老化，并将阐明性别差异的压力反应和潜在的作用， 灰色和白色物质中的GC、P4和Sgk 1。即使我们所有的工作假设都被结果所否定， 建议的研究应该对老年医学有转化价值。

Evidence indicates that prolonged/ repeated behavioral stress promotes brain aging. This is thought to be due, at least in part, to stress associated glucocorticoid (GC) secretion, which in turn binds to glucocorticoid receptors, exerting transcriptional and other effects. A key downstream mediator in this signaling pathway, serum-and- glucocorticoid kinase 1 (Sgk1) accelerates, and the female sex steroid progesterone (P4) blunts, the effects of GCs. However, despite the negative clinical consequences of chronic stress exposure with aging and/or in female subjects, little work has examined how aging may change the stress response, the mechanisms through which stress may accelerate brain aging, the degree to which stress-accelerated aging is dependent on GC, is driven by Sgk1, or is inhibited by P4. Our preliminary data suggests that hippocampal Sgk1 is upregulated by aging, stress, and GCs in white matter oligodendrocytes, and that the female sex hormone progesterone (P4) blunts the effects of stress/GCs and may serve as an endogenous protectant that is lost with age in females. To address these knowledge gaps, we propose 3 aims to investigate: the age-course of the response to chronic stress or chronic GCs in males and females; whether viral overexpression of Sgk1 exacerbates, or systemic P4 administration ameliorates, stress-accelerated aging; and whether the pharmacologic sensitivity of hippocampal tissue to GC and P4 is shifted with age or chronic stress/GC. Cognitive and anxiety-related behavior, blood hormone measures, and a novel panel of 205 hippocampal genes that are robustly changed with aging across multiple studies, will be used to test for stress/GC-accelerated aging and intervention effects, as will downstream gray and white matter Sgk1 expression and microglial response to microinjury- two processes demonstrated to be glucocorticoid sensitive and exaggerated in white vs. gray matter in preliminary data. Thus, the proposed studies will yield essentially the first comprehensive test of the hypothesis that chronic stress accelerates transcriptional brain aging and will illuminate sex differences in stress responsiveness and the potential roles of GC, P4, and Sgk1 in gray and white matter. Even if all of our working hypotheses are rejected by the results, the proposed studies should have translational value for geriatric medicine.